Igangværende forskning…INDICES

INDIvidualised drug therapy based onpharmacogenomics: focus on

carboxylesterase 1 (CES1)

Kim Dalhoff

Kim Dalhoff● Professor of Clinical Pharmacology

(toxicology), MD, DMSc, FEAPCCT● Specialist in Clinical Pharmacology and

Hepatology● Consultant at the Department of Clinical

Pharmacology, Bispebjerg andFrederiksberg Hospital & Giftlinjen(DPIC)

● E-mail: kim.peder.dalhoff@regionH.dk

Outline

● Introduction to CES1●Variation in drug response● INDICES background (key

studies)● INDICES – WP2

Carboxylesterase 1 (CES1)● Phase I enzyme involved in

hydrolysis of ester andamido-type drugs, includingactivation of prodrugs

● Encoded by a genecomposed of 14 exonsspanning 30 kb onchromosome 16

Sustrate spectrum of CES1 –metabolism and bioactivation

● Methylphenidate● Cocaine and heroin● Imidapril and derapril (angiotensin-converting

enzyme inhibitors)● Oxybutynin (anticholinergic)● Oseltamivir (avian flu)● Irinotecan● Environmental compunds such as phthalates,

pyrethroid and organophosphates

CES is involved in the hydrolysis ofseveral xenobiotics and endogenousesters and amides●CES1 (liver)●CES2 (intestines)● CES3● CES4

METHYLPHENIDATELack of response● Up to 30% of patients receiving MPH are non-respondersAdverse effectsVery common (> 10%)● Decreased appetite, stomach pain, headache and insomniaCommon (1-10%)● Weight loss● Nausea● Diarrhoea and vomiting● Cardiac effects (tachycardia, elevated systolic blood pressure and arrhythmia)Not common (0.1-1%)● Confusion● Psychosis● Breast pain and dyspnoea● Abnormal dreams● Allergic reactions

Large variation in drug responsebetween individuals

● Some patients get the desired

effects (responders)● A lot of patients only get little

effect (partially responders) orno effect at all (non-responders)

● The remaining group ofpatients get adverse drugreactions

Solution to the problems is(may be) individualization ofdrug dose and type of drug

● ”One size fits all” – ”standardtreatment”● A patient is classified into a subgroup

with a differential therapeutic response● Personalized medicine, fitted to the

single individual

Various types of genetic variation

● Single nucleotide variation● Indels (< 1kb)● Copy number variation (> 1 kb)

Structural variation

Normal

Deletion

Duplication

Triplication

Inversion

Deletions and duplications = copy nummer variationsSize is always > 1 kb

Sai et al. BJCP 2010;70:222

Sai et al. BJCP 2010;70:222

Sai et al. BJCP 2010;70:222

Sai et al. BJCP 2010;70:222

H-J Zhu et al. Am J Hum Gen 2008; 82: 1241

H-J Zhu et al. Am J Hum Gen 2008; 82: 1241

A focused study of the subject’sCES1 gene

DNA sequencing detects two coding region SNP’s inexons 4 and 6● Exon 4 (codon 143) non-conservative substitution

p.Gly143Glu● Exon 6 (codon 260) deletion leading to a frameshift

mutation p.Asp260fsp.Gly143Glu allele frequency 3.7% (white population)(Asian 0%)p.Asp260fs extremely rare (none in 925 DNA samples)

H-J Zhu et al. Am J Hum Gen 2008; 82: 1241

INDICES

CES1

WP2WP7

WP6

WP5WP4

WP3

WP1

●WP1: Drug and metabolite study●WP2: Pharmacokinetic study●WP3: Genetic study●WP4: Pharmacometabolomics●WP5: Systems pharmacology and

metabolomics●WP6: Clinical study A – ADHD●WP7: Clinical study B – CHF

WP2: Individual differences in themetabolism of drugs

● Genetic screening of 150 healthy volunteers forCES1 variants (enrichment of the study populationto increase the number of rare variants)

● Selection of 40-50 individuals based on CES1genotypes

● Pharmacokinetic study with methylphenidate andenalapril

Claus Stage, phd-student

Selection of subjects● Group 1 (n=16) Two copies of CES1A1 (control

subjects)● Group 2 (n=5) Four copies of CES1 (2 CES1A1 and 2

CES1A2● Group 3 (n=6) Subjects with pGly143Glu SNP● Group 4 (n=2) Three copies of CES1 and CES1A2

(the variant with increased promoter activity)● Group 5 (n=4) Subjects with the CES1A1c variant● Group 6 (n=10) Tree copies of CES1 and CES1A2

(variants with normal promoter)To be continued…

Outline● Introduction to CES1● Variation in drug response● INDICES background● INDICES – WP2 THANKS FOR YOURATTENTION ☺☺